APPLICANT'S ABSTRACT: A series of studies is proposed in normal human subjects and in subjects with histories of drug abuse to investigate several major behavioral- pharmacological effects that caffeine shares with classic drugs of abuse: physical dependence/tolerance, discriminative stimulus effects, and reinforcing effects. Studies will be conducted in both non- residential and residential laboratory research settings. Drugs will be administered in capsules or by intravenous injection under double- blind conditions and the effects of drug administration or termination of chronic dosing will be assessed using subjective, behavioral and/or physiological measures. A series of three studies will extend the investigators' work on caffeine physical dependence. The first three of these will provide information about pharmacological specificity and mechanisms of action by using variations on drug discrimination procedures to compare caffeine with theophylline, d-amphetamine and triazloam. One study will investigate individual differences in sensitivity to the discriminative effects of caffeine and these other compounds. Two other studies will characterize the profiles of generalization in subjects trained on discriminations involving either low-dose caffeine vs. placebo or low-dose d-amphetamine vs. placebo.Two other studies will use discrimination procedures as a baseline for characterizing caffeine tolerance and for attempting to enhance caffeine reinforcement. The final discrimination study will involve application of the investigators' low-dose caffeine discrimination procedures to develop a low-dose oral cocaine discrimination model in subjects with histories of drug abuse. A final set of three studies will characterize subjective, psychomotor performance, physiological and reinforcing effects of intravenously administered caffeine. Two studies in subjects with histories of drug abuse will investigate the effects of caffeine dose and intravenous injection duration, and will compare caffeine with the other psychomotor stimulant drugs cocaine, d-amphetamine and nicotine. A final study will use identical procedures to compare the intravenous administration of caffeine and nicotine in normal subjects. This research with caffeine and other classic psychomotor stimulants should advance understanding of behavioral-pharmacological mechanisms underlying drug abuse/dependence. Given the widespread licit use of caffeine, this project will also be of clinical importance in identifying determinants of vulnerability to caffeine physical dependence and reinforcement in the general population and to developing caffeine- use reduction or cessation programs as well as programs for minimizing caffeine-associated health risks.